HCV was cloned and characterized about 15 years ago by Choo and colleagues (see Science 244, (1989), 359-362). HCV belongs to the family Flaviviridae and comprises an enveloped nucleocapsid and a single-stranded RNA genome of positive polarity (see Bartenschlager et al., Antiviral Res. 60, (2003), 91-102). HCV is transmitted primarily by blood, blood products and vertical transmission during pregnancy. Introduction of diagnostic tests for screening blood products has significantly reduced the rate of new infection.
Still, HCV remains a serious medical problem. There are currently about 170 million people infected with HCV. The initial course of infection is typically mild. However, the immune system is often incapable of clearing the virus, and people with persistent infections are at a high risk for liver cirrhosis and hepatocellular carcinoma (see Poynard et al., Lancet 349, (1997), 825-832).
There is no vaccine available, and therapeutic options are very limited (see Manns et al., Indian J. Gastroenterol. 20 (Suppl. 1), (2001), C47-51; Tan et al., Nat. Rev. Drug Discov. 1, (2002), 867-881).
Current therapy is based on a combination of interferon alpha and ribavirin. This therapy produces a sustained anti-viral response in 85-90% of patients infected with genotypes 2 and 3, but, unfortunately, only in about 45% of patients infected with the prevalent genotype 1. Furthermore, side effects are significant and include myalgia, arthralgia, headache, fever, severe depression, leucopenia and haemolytic anaemia.
Clearly, additional therapies, with a higher antiviral activity and a better safety profile, are required for the treatment of HCV infection, particularly e.g. in the case of the prevention of HCV recurrence. In order to establish the safety profile, criteria such as low cytotoxicity and cytostatic and high selectivity index are particularly relevant for clinical treatment of HCV infection.
A novel approach for the treatment of HCV infection using cyclosporins was recently described by clinical observations (see Teraoka et al., Transplant Proc., 1988, 20 (3 suppl 3), 868-876, and Inoue et al. J Gastroenterol, 2003, 38, 567-572). Recently it was shown that Cyclosporin A (CsA) inhibited the in vitro intracellular replication of an HCV subgenomic replicon at clinically achievable drug concentrations (see Watashi et al., Hepatology 38, 2003, 1282-1288, and Nakagawa et al., BBRC 313, 2004, 42-47). Both groups suggested that the anti-HCV effect of CsA was not associated with immunosuppressive activity based on observations made with the use respectively of an immunosuppressive macrolide, i.e. the compound known under the name FK 506 and a non-immunosuppressive Cyclosporin A derivative, i.e. the compound known under the name NIM 811 or [Melle]4-CsA. Nakagawa et al. consider that expanding applications of CsA may cause substantial problems due to its well-known immunosuppressive properties and suggest that one solution to overcome this problem would be to consider the use of non-immunosuppressive cyclosporin analogs.
During the last 15 years, a number of medicinal chemistry studies have been conducted with the aim to identify such non-immunosuppressive cyclosporin analogs and compound NIM 811 is one of the most representative compounds having such a property.
NIM 811, along with 9 other Cyclosporin A derivatives, were reported by Ko et al. in patent application EP 0 4840 281 for their non-immunosuppressive properties and were considered as being potentially useful in the treatment of HIV infection and the prevention of AIDS. The design of those derivatives involved the modification of the amino-acids in 4- and/or 5-positions of Cyclosporin A.
By modifying amino-acids in 2- and/or 6-positions of Cyclosporin A, Sigal et al. synthesised a total of 61 cyclosporin analogs and observed that such chemical modifications induce a decrease in the immunosuppressive activity (see Sigal et al., J. Exp. Med., 173, 1991, 619-628).
Further attempts for modifying amino-acid in 3-position of Cyclosporin A in order to obtain non-immunosuppressive compounds were described in particular by Barrière et al., in WO 98/28328, WO98/28329, and WO 98/28330.
Wenger et al. have designed a series of compounds that differ from Cyclosporin A in position 3, in which they contain an N-methylated, nonbulky hydrophobic or neutral amino acid other than a glycine, and in position 4, in which they contain an N-methylated or N-ethylated hydrophobic or neutral amino acid other than a leucine and they report that those compounds have a high potency to inhibit HIV-1 replication and essentially lack immunosuppressive activity (see International patent application WO 00/01715 and Tetrahedron Lett., 41, (2000), 7193-6).